Over the last 50 years the treatment of a variety of human illnesses has vastly improved with the identification of active drugs and their introduction into clinical use. While perhaps not as dramatic as penicillin or insulin, various clauses of agents, nonetheless, have improved the therapy and/or prognosis of common disorders, including (1) mental illness, especially schizophrenia (e.g. phenothiazines) and major depressive disease (e.g. tricyclic antidepressants and newer, non-tricyclic agents such as fluoxetine); (2) hayfever, asthma, urticaria and other acute allergic disorders (e.g. H.sub.1 -antagonists); (3) peptic ulcer disease (e.g. H.sub.2 -antagonists); (4) fungal diseases (imidazoles e.g. clotrimazole, ketoconazole); (5) breast cancer (e.g. tamoxifen); and (6) hypertension, arrythmia and angina (.beta.-adrenergic antagonist). While these seemingly disparate classes of drugs have differing chemical structures, interactions, and indicated uses, in most cases the mechanisms by which they produce their effects are incompletely understood.
For example, although the phenothiazines are known to be antagonists of dopamine (D.sub.2) receptors, interactions at many other intracellular sites, including calmodulin, protein kinase C and calcium channels may be important to their activity. Similarly, while antidepressants are known to decrease the uptake of biogenic amine neurotransmitters into nerve endings (especially aerotonin and norepinephrine) thereby increasing their concentration in synapses, a good correlation between potency to inhibit the uptake of any specific amine and potency as antidepressant agents has not been shown.
As another example, while histamine antagonists appear to produce their antiallergic and antiacid effects through binding H.sub.1 and H.sub.2 receptors, respectively, P450 microsomal enzymes, important in the metabolism of lipids and eicosanoids, have been identified as a major site of binding of the former, as well as of imidazoles. In addition, antidepressant drugs, such as doxepin, do not bind H.sub.2 receptors, yet are potent to inhibit acid secretion. As a final example, the antiestrogeni tamoxifen is thought to inhibit breast cancer proliferation through binding estrogen receptors. Yet, it has been reported that tamoxifen is effective in 10% of breast cancers negative for estrogens receptors, suggesting additional mechanisms of action.
Recently, there has been described the existence of unique intracellular histamine receptors, designated H.sub.IC, in brain membranes and liver microsomes. The paradiphenyl-methane derivative, N,N-diethyl-2-[4-(phenylmethyl)-phenoxy]-ethanamine.HCl (DPPE) is a potent antagonist of H.sub.IC. Surprisingly, the other classes of drugs mentioned above, including phenothiazines, H.sub.1 antagonists, serotonin (5HT.sub.1, and 5HT.sub.3) antagonists, triphenylethylene antiestrogens and .beta.-adrenergic antagonists also compete, with varying degrees of affinity, for both DPPE and H.sub.IC binding. While H.sub.2 antagonists and other imidazoles do not compete for DPPE binding, they do compete for H.sub.IC, but with lower affinity than for compounds which bind both AEBS and H.sub.IC.
Through binding H.sub.IC, histamine functions as Man intracellular messenger to mediate aggregation in blood platelets and is implicated in the proliferation of normal and malignant cells. A second messenger role for histamine at H.sub.IC also has been postulated in estrogen action and in brain function. Thus, it is possible that H.sub.IC binding may be common to the action of many classes of drugs, including phenothiazines, antidepressants, antiestrogens, histamine (H.sub.1, H.sub.2, H.sub.3) antagonists, serotonin (5HT.sub.1, 5HT.sub.3) antagonists, .beta.-adrenergic antagonists and antifungal agents.
Recently, in published International patent application WO 92/11035, U.S. Ser. No. 711,957 filed Jun. 7, 1991), there is described a novel method of treatment for cancer, combining DPPE or its analogues with chemotherapy drugs, such as doxorubicin (Adriamycin.TM.). In animals and humans, this method of treatment results in the protection of normal stem cells, including bone marrows and mucosal epithelium, while enhancing the anticancer effects of chemotherapy on malignant cells. Although the mechanism of this differential action is not fully understood, in vitro studies indicate that DPPE inhibits normal cell proliferation, in the absence of toxicity, but stimulates malignant cell proliferation and cytotoxicity. Increased response to chemotherapy has been demonstrated in tumor-bearing animals treated concurrently with DPPE. In addition, DPPE also directly cytoprotects normal gut mucosa in vitro, an effect related to DPPE-induced increases in endogenous levels of the protective prggtaglandin, PGI.sub.2, and reversed by indomethicin.